Introduction

The SPYRAL HTN-ON trial is the other half of the SPYRAL program, a sibling if not a twin of the SPYRAL HTN-OFF trial. The methods and rationale of both the trials are described in this paper. Unlike the SPYRAL-OFF, the SPYRAL-ON allowed patients to be on their medications - but up to 3 medications, not like the initial renal denervation (RDN) studies with resistant hypertension. From the previous discussion - this would open up the trial to the threat of non-adherence, or rather variable adherence creating noise and a possible null result. Hence, a key aspects of this trial was assessment of the outcome, blood pressure as measured by ambulatory BP monitoring (ABPM), after direct observed therapy, both for baseline and for follow up.

The Study

Methods

This was a multicentre study, recruiting patients from 25 centres globally, from US, Europe, Australia and Japan.

Patients were on one, two, or three (but not more) standard antihypertensive drugs. Medications were required to be prescribed at 50% or more of the maximum manufacturer’s recommended dosage. Standard antihypertensive drugs meant a thiazide-type diuretic, a dihydropyridine calcium channel blocker, an ACE-inhibitor or angiotensin receptor blocker (ACE-I or ARB), or a β blocker.

There was an initial screening visit to confirm eligibility and that the medical regimen had not been changed for the last 6 weeks. A second screening visit followed, with blood/urine testing for drug levels, direct observed administration of BP medications, followed by the ABPM study. Only if the ABPM (after direct observed therapy) confirmed eligibility were they randomised into the trial.

Fig S1 from Kandzari et al, Lancet 2018

Randomisation to renal denervation or sham procedure was stratified by trial centre at a 1:1 ratio.

Intervention

Following randomisation patient either underwent a renal angiogram (sham procedure) or renal angiogram with subsequent radiofrequency ablation renal denervation procedure. During the procedures (renal angiogram alone or followed by renal denervation) masking was maintained by the use of conscious sedation, blindfolding, music, and patients’ lack of familiarity with the procedures. Like in SPYRAL-OFF, ablation was done with the multielectrode catheter, with all arteries (including branches) measuring between 3 and 8 mm targeted for ablation.

The blinded trial staff did all follow-up visits and the patient’s referring or managing physicians were unaware of a patient’s treatment assignment.

Outcomes and Analyses

The primary outcome for efficacy was change in BP from baseline to 6 months on the basis of ABPM - hence both baseline and 6 month readings occured after direct observed therapy (as recommended in the previous analysis). Similar to SPYRAL-OFF, there was no formal sample size calculation or effect size estimate. The objective of the study was to assess if renal denervation could safely and effectively lower BP at all, compared to sham controls. The protocol allowed up to 110 patients to be randomly assigned with prospectively planned interim analyses after 40, 60, and 80 patients completed 3 months of follow up. Because the current study prespecified that patients should be maintained on the same medication regimen through 6 months follow-up, analysis of the 80 patient cohort was then performed to assess the pattern and progression of blood pressure change over time.

Funding

The trial was funded by the maker of the Symplicity and Spyral catheters: Medtronic. They were responsible for data collection and analysis as well as assisted in figure and table generation, copy editing, and formatting.

Results

Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). The figure below shows that many enrolled patients were excluded during the screening visits, mostly since their BP did not qualify. A few patients met escape criteria.

Figure 1 from Kandzari et al, Lancet 2018.

Similar to SPYRAL OFF, the baseline characteristics show these were not high risk patients - around 50 years old, very few with diabetes or other comorbid conditions. The baseline office BP was 165/100 and the ABPM was 150/97 mm Hg. About half the patients were on 3 medications, and the remaining on either 1 or 2 medications.

There was a lot of burning involved - as shown in this supplementary table, requiring an hour or so. Presumably the sham procedure also meant piped music and sounds for an hour, since the blinding index was 0.78 at discharge and 0.64 at 6 months (> 0.5 = good blinding).

Table S2 from Kandzari et al, Lancet 2018

The change in blood pressure was significantly greater at 6 months in the renal denervation, as can be seen from the figure below.

Figure 2 from Kandzari et al, Lancet 2018

The mean change in ambulatory BP (remember this was after direct observed therapy) shows a nice overall 24 hour decrease in BP from baseline.

Figure 4 from Kandzari et al, Lancet 2018

Though average blood pressure fell, not all patients responded to RND (See figure S3 below).

Figure S3 from Kandzari et al, Lancet 2018

Safety: all patients underwent a duplex ultrasound at 6 months, with follow up imaging if deemed necessary. There were no adverse events reported during the (relatively short) follow up of 6 months.

Adherence results

In a rigorously done clinical trial with lots of TLC provided to the patients roughly half of them were not taking their medications as prescribed.

Given the extensive assessment of adherence, these results are worthy of some closer examination. To reiterate, the primary outcome mentioned above - of 24-hour ABPM, was based on change from baseline with direct observed therapy of that day's BP medications. But we have data on overall adherence at baseline, 3 and 6 months, based on plasma and urine samples. Roughly half the patients were not taking all their meds.

Figure S2 from Kandzari et al, Lancet 2018

If the authors did not do direct observed therapy - one wonders what the results might have been? The authors did conduct a separate subgroup analysis by adherence - showing some interesting results, below.

Figure S4 from Kandzari et al, Lancet 2018

Discussion

Overall, there was a clear demonstration of the efficacy of RDN in lowering BP compared to sham procedure on the background of up to three antihypertensive drugs. No safety signals were observed in the study. Adherence with prescribed medical treatment was approximately 60% with highly variable individual patient adherence at all timepoints.

Strengths of the study include

Use of sham procedures and effective blinding

Use of rigorous BP measurement (ABPM at baseline and follow up, after direct observed therapy)

Significant effort made to ensure adequate nerve ablation based on procedural details

Limitations include

Small sample size, with no a priori assumption of effect size (deliberate)

Not a high risk population (again, planned and deliberate)

Significant non-adherence introducing confounding in the analysis

Check out our overall summary for comparisons with the other studies and #NephJC discussion plan.